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首页> 外文期刊>Development >Abrogation of the Cripto gene in mouse leads to failure of postgastrulation morphogenesis and lack of differentiation of cardiomyocytes.
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Abrogation of the Cripto gene in mouse leads to failure of postgastrulation morphogenesis and lack of differentiation of cardiomyocytes.

机译：小鼠中Cripto基因的废除会导致胎后形态发生失败和心肌细胞缺乏分化。

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摘要

Cripto-1(Cr1) protein encoded by the tdgf1 gene, is a secreted growth factor that is expressed early in embryonic development and is re-expressed in some tumors of the breast and colon. During embryonic development, Cr1 is expressed in inner cell mass cells and the primitive streak, and later is restricted to the developing heart. To investigate the role of Cr1 during mouse development, mice were generated that contain a null mutation of both Cr1 genes, derived from homologous recombination in embryonic stem cells. No homozygous Cr1-/- mice were born, indicating that Cr1 is necessary for embryonic development. Embryos initiated gastrulation and some embryos produced mesoderm up to day E7.5. Increasingly aberrant morphogenesis gave rise to disordered neuroepithelium that failed to produce a recognizable neural tube, or head-fold. Although some biochemical markers of differentiating ectoderm, mesoderm and endoderm were expressed, all the cardiac-specific markers were absent from day E8.7 embryos: (&agr;)MHC, betaMHC, MLC2A, MLC2V and ANF, whereas they were expressed in wild-type embryos. The yolk sac and placental tissues continued development in the absence of the embryo until day E9.5 but lacked large yolk sac blood vessels. Chimeric mice were constructed by microinjection of double targeted Cr1(-/- )embryonic stem cells into normal C57BL/6 blastocysts. The Cr1 produced by the normal C57BL/6 cells fully rescued the phenotype of Cr1(-/-) cells, indicating that Cr1 protein acted in a paracrine manner. Cells derived from the embryo proliferated and migrated poorly and had different adhesion properties compared to wild type. Therefore, lethality in the absence of Cr1, likely resulted largely from defective precardiac mesoderm that was unable to differentiate into functional cardiomyocytes.
机译：由tdgf1基因编码的Cripto-1（Cr1）蛋白是一种分泌的生长因子，在胚胎发育的早期表达，并在乳腺和结肠的某些肿瘤中重新表达。在胚胎发育过程中，Cr1在内部细胞团细胞和原始条带中表达，后来被限制在发育中的心脏。为了研究Cr1在小鼠发育过程中的作用，产生了包含两个Cr1基因无效突变的小鼠，这些突变源自胚胎干细胞中的同源重组。没有纯合的Cr1-/-小鼠出生，表明Cr1是胚胎发育所必需的。直到E7.5天，胚胎才开始进行胃成膜，有些胚胎产生了中胚层。越来越多的异常形态发生导致混乱的神经上皮细胞，无法产生可识别的神经管或头部折叠。尽管表达了一些区分外胚层，中胚层和内胚层的生化标志物，但在E8.7天的胚胎中不存在所有心脏特异性标志物：（agr）MHC，betaMHC，MLC2A，MLC2V和ANF，而它们在野生型中表达。类型胚胎。在没有胚胎的情况下，卵黄囊和胎盘组织持续发育直到第E9.5天，但卵黄囊的血管却没有。通过将双重靶向的Cr1（-/-）胚胎干细胞显微注射到正常C57BL / 6胚泡中来构建嵌合小鼠。正常C57BL / 6细胞产生的Cr1完全拯救了Cr1（-/-）细胞的表型，表明Cr1蛋白以旁分泌的方式起作用。与野生型相比，源自胚胎的细胞增殖和迁移不良，并且具有不同的粘附特性。因此，不存在Cr1时的致死性可能主要是由于不能分化为功能性心肌细胞的有缺陷的心脏前中胚层所致。

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